Throughout and within this disclosure, various publications, patents, published patent applications and references are identified by first author and date, within parentheses, patent number, publication number or by web address. If the complete bibliographic citation is not provided after the publication or reference, it is at the end of the specification, immediately preceding the claims. The disclosures of all publications, references and information provided at the web addresses are hereby incorporated by reference into this disclosure to more fully describe the state of the art to which this invention pertains.
Hyperproliferative cells grow at a rate over that of normal or healthy cells. The presence of these abnormal cells has been linked to many pathologies, e.g., cancer, infectious disease, autoimmune disorders and inflammatory conditions or diseases. In many instances, they are useful diagnostic indicators. In other instances, subcellular changes linked to progression toward the hyperproliferative state are useful prognostic indicators of disease progression or its curative treatment.
Cancer cells are hyperproliferative, i.e., characterized by uncontrolled growth, de-differentiation and genetic instability, that express as aberrant chromosome number, chromosome deletions, rearrangements, loss or duplication beyond the normal diploid number. (Wilson, J. D. et al. (1991)). This genomic instability may be caused by several factors. One of the best characterized is the enhanced genomic plasticity which occurs upon loss of tumor suppressor gene function (e.g., Almasan, A. et al. (1995a) and Almasan, A. et al. (1995b)). The genomic plasticity lends itself to adaptability of tumor cells to their changing environment, and may allow for the more frequent mutation, amplification of genes, and the formation of extrachromosomal elements (Smith, K. A. et al. (1995) and Wilson, J. D. et al. (1991)). These characteristics provide for mechanisms resulting in more aggressive malignancy because they allow tumors to rapidly develop resistance to natural host defense mechanisms, biologic therapies (See Wilson, J. D. et al. (1991) and Shepard, H. M. et al. (1988)), as well as to chemotherapeutics (See Almasan, A. et al. (1995a); and Almasan, A. et al. (1995b)).
The heterogeneity of malignant tumors with respect to their genetics, biology and biochemistry as well as primary or treatment-induced resistance to therapy mitigate against curative treatment. Moreover, many anticancer drugs display only a low degree of selectivity, causing often severe or even life threatening toxic side effects, thus preventing the application of doses high enough to kill all cancer cells. Searching for anti-neoplastic agents with improved selectivity to treatment-resistant pathological, malignant cells remains, therefore, a central task for drug development.
The function of tumor suppressor genes is a major focus of recent attempts to develop innovative therapeutics for the treatment cancer. The products of tumor suppressor gene expression are generally characterized as negative regulators of cell proliferation (Knudson, A. G. (1993) and Weinberg, R. A. (1995)). Thus, therapeutic approaches to date include gene therapies to restore inactive or missing tumor suppressor function in cancer cells to re-establish normal cellular function or induce apoptosis (Clayman, G. L. (2000) and Knudson, A. G. (1993)).
Loss of RB/p16 function can result in similar proinflammatory, proliferative and dedifferentiating effects on cells (Carson, R. A. and Haneji, N. (1999); Shim, J. et al. (2000); Wolff, B. and Naumann, M. (1999); DiCiommo et al. (2000)), and alteration in cell-cell interactions (Plath et al. (2000)). Inactivation of tumor suppressor function by somatic mutation or via interaction with virally-encoded proteins is proposed to contribute to the proliferative/inflammatory aspect of athersclerosis, restenosis or other hyperproliferative diseases (Tanaka, K. et al. (1999); Aoki, M. et al. (1999); Guevara, N. V. et al. (1999); and Iglesias, M. et al. (1998)). Finally, the expression of the proinflammatory cytokine, macrophage inhibitory factor (MIF), may be capable of inactivating p53 function in some cell types (Hudson, J. D. et al. (1999); Cordon-Cardo, C. and Prives, C. (1999); and Portwine, C. (2000)).
Functional loss of tumor suppressor genes also has been linked to inflammatory or autoimmune diseases that have cellular hyperproliferation as one of their characteristics (Cordan-Cardo, C. and Prives, C. (1999)) and/or defective apoptosis (programmed cell death) (Mountz, J. D. et al. (1994)). These include: rheumatoid arthritis, systemic lupus erythmatosus, psoriatic arthritis, reactive arthritis, Crohn's disease, ulcerative colitis and scleroderma. Table 1 lists literature examples which suggest that such a link may exist.
TABLE 1Literature Examples Suggesting that Biological Expression of p53 TumorSuppressor Mutation/Inactivation Relates to Noncancer HyperproliferativeDisease, Autoimmune Disease and Inflammation.ImpactDisease EffectReferenceIncreased IL6ProliferationHan, et al. (1999)InflammationRheumatoid ArthritisIncreasedTissue DegradationSun, Y. et al.metalloproteinases(2000)Increased proliferation ofRheumatoid arthritisAupperle, K. R. etal. synovial cells(1998)Genetic instabilityChronic inflammationTak, P. P. et al.(2000)and disease progressionUlcerative colitisLang, S. M. et al.(1999)Increased expression ofProliferationBanerjee, D. et al.E2F regulated genesDrug resistance(1998)(TS, DHFR)Multiple autoimmuneand inflammatorydiseasesViral proteins expressionAthersclerosisTanaka, K. et al.leading to p53(1999)inactivationIncreased angiogensisSupports hyper-Zhang, L. et al.proliferative States, ex.(2000)enablingatheromaorpannusformation.
The hyperproliferative phenotype has also been linked to resistance to chemotherapy in cancer, infectious disease, autoimmune disease and inflammatory conditions. Some hyperproliferative cells overexpress an intracellular enzyme that is related to any of a loss of tumor suppressor gene product function, drug resistance or genetic instability. A number of cellular mechanisms are involved in drug resistance, e.g., altered metabolism of the drug, impermeability of the cell with regard to the active compound or accelerated drug elimination from the cell, altered specificity of an inhibited enzyme, increased production of a target molecule, increased repair of cytotoxic lesions, or the bypassing of an inhibited reaction by alternative biochemical pathways. Enzymes activated or overexpressed and related to drug resistance include, but are not limited to thymidylate synthase (TS) (Lönn, U. et al. (1996); Kobayashi, H. et al. (1995); Jackman, A. L. et al. (1995)), dihydrofolate reductase (Banerjee, D. et al. (1995) and Bertino, J. R. et al. (1996)), tyrosine kinases (TNF-α, Hudziak, R. M. et al. (1988)) and multidrug resistance (Stühlinger, M. et al. (1994)); Akdas, A. et al. (1996); and (Tannock, I. F. (1996)); and ATP-dependent multidrug resistance associated proteins (Simon, S. M. and Schnindler, M. (1994)). Alternatively, resistance to one drug may confer resistance to other, biochemically distinct drugs. Amplication of certain genes is involved in resistance to chemotherapy. Amplification of dihydrofolate reductase (DHFR) is related to resistance to methotrexate while amplification of the gene encoding thymidylate synthase is related to resistance to tumor treatment with 5-fluoropyrimidine.
Overexpression of enzymes encoded by human and animal pathogens, and in which the inhibitors have failed due to development of resistance, also has been linked to disease. Indeed, resistance to antibiotics is a major health care problem. In infectious disease, most drug resistance is enzyme mediated. Typically, an enzyme expressed by the infectious agent rapidly modifies the chemotherapeutic or antibiotic, thereby abolishing its therapeutic activitiy. Amplified expression of beta-lactamases accounts for more than one-third of all beta-lactam antibiotic resistant isolates (Felmingham and Washington (1999)), including the majority of resistant Haemophilis influenza (upper respiratory infections) and Moraxella catarrhalis (otitis media). In addition, genes conferring resistance to various alternative types of antibiotics occur in nature and have become increasing common in populations of infectious organisms. Recently, infectious agents carrying sets of genes simultaneously conferring resistance to multiple antibiotic agents have arisen making treatment by traditional antibiotic therapy difficult.
Thus, novel compounds and therapies are necessary overcome the limitations of current therapies. This invention satisfies this need and provides related advantages as well.